Use of 2-(chloro or trichloromethyl)-4-amino-6-substituted - s - triazines for inducing depressant effects in animals



United States Patent USE OF Z-(CHLORO 0R TRICHLOROMETHYL)-4-AMINO-lS-SUBSTITUTED s TRIAZINES FOR IN- DUCING DEPRESSANT EFFECTS INANIMALS Jiro K. Kodama and James R. Albert, Modesto, Calif., assignorsto Shell Oil Company, New York, N.Y., a corporation of Delaware NoDrawing. Continuation-impart of abandoned applications Ser. No. 498,116,and Ser. No. 498,118, Oct. 19, 1965. This application Mar. 27, 1968,Ser. No. 716,352

Int. Cl. A61k 27/00 US. Cl. 424-249 ABSTRACT OF THE DlSCLOSURE Use of 2(chloro or trichloromethyl) 4 amino 6- substituted-s-triazines forinducing depressant effects in animals.

This application is a continuation-in-part of copending applicationsSer. Nos. 498,116 and 498,118, both filed October 19, 1965 and both nowabandoned.

BACKGROUND OF THE INVENTION This invention relates to a method ofinducing depressant effects in animals using certain s-triazines. Moreparticularly itrelates to the use of certain s-triazines as analgesics,muscle relaxants, anticonvulsants and tranquilizers and topharmaceutical .and veterinary compositions containing such triazines.

A considerable number of naturally occurringg alkaloids and syntheticchemicals are available as useful analgesics, anticonvulsants and musclerelaxants. Repeated administration of many such analgesics creates thepotential danger of drug addiction. The need for effective analgesicswhich minimize the hazards of drug addiction has long been recognized.

SUMMARY OF THE INVENTION It is an object of the present invention toprovide a novel method for inducing depressant effects in mammals. Thesedepressant effects include sedative, analgesic, muscle relaxant,anticonvulsant and tranquilizing effects. Another object of theinvention is to provide a novel method of pain control with minimumhazard of drug addiction. Yet another object is to provide a novelmethod for inducing depressant effects in mammals with certain Z-(chloroor trichloromethyl) 4 amino 6 substituted s triazines. The provisionsfor supplying the art with novel pharmaceutical and veterinarycompositions capable of inducing neurological depressant effects inmammals forms another object.

These and other objects are accomplished by administering to a mammal aneltective dosage of a Z-(chloro or trichloromethyl) 4 amino 6substituted s triazine of the formula wherein X is -CI or -CCl Y is -NRRin which R is hydrogen, alkyl of 1-3 carbon atoms or hydroxyalkyl of 1-4carbon atoms,

R is alkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms,chloroalkyl of 1-3 carbon atoms or methoxyalkyl of 2-5 carbon atoms andR and R together with the nitrogen may represent piperidino; and

12 Claims 3,549,759 Patented Dec. 22, 1970 Z is l a Z is OO-R3 in whichR is alkyl of 1-3 carbon atoms and R is hydrogen or alkoxycarbonyl of upto 4 carbon atoms;

11 1 I-(alkylene)-R in which R, is dialkylaminocarbonyl of up to 7carbon atoms or alkylsulfinyl. of 1-3 carbon atoms and alkylene is of1-3 carbon atoms;

t -N-R5OI-I in which R is alkylene of l-4 carbon atoms;

-(oH ),..-N

2 in which 111 is 2-4; CCl -Oalkyl in which alkyl is of 1-3 carbonatoms;

N-alkylene-Ol in which alkylene is of 1-3 carbon atoms;

s -N=( 3CH2-CN in which R is alkyl of 1-3 carbon atoms.

Representative species of the above s-triazines are:

I (14) 2-trichloromethyl-4-piperidino-6-(2-(l-piperidino)ethyl)-s-triazine (15)2,4-bis-(trichloromethyl)-6-(diethanolamino-striazine (16)2,4-bis-(trichloromethyl)-6-(3-hydroxypropylamino)- s-triazine (17)2,4-bis-(trichloromethyD-6-(2-chloroethylamino)-striazine (18)2,4-bis-(trichloromethyl)-6-(3-chloropropylamino)- s-triazine (19)2-trichloromethyl-4-piperidino-6-methoxy-s-triazine (20)2-trichlor-omethyl-4,6-bis-(2-chloroethylamino)-striazine (21)2-trichloromethyl-4-(2-hydroxypropylamino)-6- anilino-s-triazine (22)3-(4-chloro-6-ethylamino-s-triazin-2-ylimino) butyronitrile (23)3-(6-tert-butylamino-4-chloro-s-trazin-2-ylitmino) butyronitrileCompositions according to the present invention also comprise apharmaceutical carrier which may either be solid material or a liquid.Preparations for oral administration can be liquids or solids or anycombination of these forms, such as syrups, elixirs, powders, capsules,or tablets. Preparations for administration of the active agent in unitdose form can be powders, compressed tablets, or a powder enclosed in asuitable capsule of absorbable material such as gelatin. The powders orcompressed tablets may also comprise suitable excipients and/ ordiluents such as starch, lactose, stearic acid, magnesium stearate,dextrin or polyvinylpyrrolidone.

Preparations for topical application may be in the form of a liquid, apowder, a salve, or as an aerosol.

Preparations for parenteral administration may be sterile solutions orsuspensions in liquids such as water, physiological saline, benzylalcohol, ethyl oleate, methylcellulose, dimethyl sulfoxide or otherliquid excipients known in the pharmaceutical and veterinary formulationart.

Any of the above preparations may contain the triazines of the inventionor may contain in addition other pharma-ceutically active agents. Forexample, for topical application it may be desirable to include agermicide and/ or a fungicide.

The unit dosage or therapeutically effective quantity of the triazinesused according to this invention as analgesics, muscle relaxants,anticonvulsants and/ or tranquilizers can vary over wide limits. Fororal or parenteral administration in some cases, as little as 0.01milligram of the active material per kilogram of body weight can beeffective in the reduction of pain or in effecting sedation and musclerelaxation, while seldom will a dosage in excess of about 500 milligramsper kilogram of body weight be required. In general, for oraladministration, the elfective dosage will be from 1.0 to 200 milligramsper kilogram of body weight, while for parenteral administration, theeffective dosage will be from about 0.10 to about 100 milligrams perkilograms of body weight. Each dosage unit formeach capsule, tablet,ampoule, or prescribed dose-can contain from about 1 percent to about 95percent active material, based upon the total weight of the formulationand preferably contains from about 2.5 percent to about 50 percent ofthe active material, on the same basis. Of course, it is possible toadminister the therapeutics without the use of a pharmaceutical carrier.

The therapeutic agents used according to the invention can beadministered either prior to or after the onset of the condition to betreated, such as when they are used as: analgesics for the ameliorationof pain; motor depressants or tranquilizers to relieve nervous tension;central depressants to reduce hyperexcitability and induce sedation; oras muscle relaxants for relief from pain and discomfort of disordersinvolving muscle spasms.

PREPARATION The s-triazines of this invention may be prepared by any ofthe conventional methods known in the art for preparing these types ofs-triazines. The following descriptions are illustrative of some of themethods that may be used.

The starting material for most of the s-triazines disclosed herein is2,4,6-tris-trichloromethyl-s-triazine while for some of the others achloro-s-triazine is used. From these s-triazines the various compoundsof the invention are prepared by replacement of the trichloromethyl orchloro groups with the various substituents depicted in Formula I.

Thus, the alkylamino, hydroxyalkylamino, methoxyalkylamino andpiperidino substituents are readily introduced into the s-triazines ofthe invention by replacement of the chloro or trichloromethyl group on achloro or trichloromethyl-s-triazine. This method involves heating thechloro or trichloromethyl-s-triazine in an organic solvent such as anether or lower alkanol with a molar excess of the appropriatealkylamine, hydroxyalkylamine, methoxyalkylamine or piperidine. Thehydroxyalkylamine-s-triazines are readily converted tochloroalkylamino-s-triazines by reaction with thionyl chloride in anorganic solvent such as an ether or aromatic hydrocarbon at moderatetemperatures.

The alkoxycarbonyloxyalkyl s triazines may be prepared by the methodsdescribed in US. 3,264,293. The s-triazines described therein are thenused to prepare the s-triazines of this invention. Thea-hydroxyalkyl-s-triazines (C(OH)R R may be prepared by reaction of thealkoxycarbonyloxyalkyl-s-triazine in a lower alkanol solvent at thereflux temperature with a barium alkanolate prepared by reacting bariumhydroxide in hot alkanol, preferably methanol, and separating thecarbonate from the barium alkanolate.

The dialkylaminocarbonylalkylamino s triazines may be prepared byconverting a corboxyalkylamino-s-triazine to the acid chloride usingthionyl chloride as the acylating agent. The resulting acid halide isthen reacted in a halo genated hydrocarbon diluent with a molar excessof a dialkylamine to form the dialkylaminocarbonylalkylaminos-triazine.The carboxyalkylamino s triazine is prepared by heating an appropriateaminoalkanoic acid with a trichloromethyl-s-triazine in a lower alkanolsolvent in the presence of sodium.

The alkylsulfinylalkylamino s triazines are prepared by reaction of achloro-s-triazine with an appropriate alkylsulfinylalkylamine in anorganic solvent, preferably a ketone.

The piperidinoalkyl s triazines are readily prepared by reacting analkenyl-s-triazine with piperidine.

The anilino-s-triazines are prepared by heating a trichloromethyl striazine with a solution of sodium in a lower alkanol.

The anilino-s-triazines are prepared by heating atrichloromethyl-s-triazine with aniline and sodium hydroxide.

The last group of s-triazines, those containing a substituent, areprepared by heating a chloro-s-triazine with an appropriateiminoacylonitrile CIIZCN in an ether solvent.

The following examples illustrate some of the methods for preparing thes-triazines of the invention.

Example I g. of 2-trichloromethyl-4-ethyla1nino-6-(l-methyl-l-(ethoxycarbonyl) ethyl)-s-triazine was dissolved and heated in 300 ml.methanol. 72 g. Ba(OH) was dissolved in 400 ml. of heated methanol andthe BaCO filtered off. This solution was then gradually added to theboiling solution of s-triazine over a period of 3 hours.

The reaction mixture was concentrated and the residue added, whilestirring, to dilute HCl, liberating C0 The water-insoluble part wasdissolved in methylene chloride and after washing, the solution wasconcentrated to a neutral reaction. The residue is triturated withwater, yielding the crystalline 2-trichloromethyl 4 ethylamino-6-(1-methyl 1 hydroxyethyl)-s-triazine, M.P. 80-82 C.

6 Example V 34.2 g. (0.1 mol) of2,6-bis-trichloromethyl-4-vinyl-striazine was added to 42.5 g. (0.5 mol)of piperidine and heated to 60 C. After standing overnight, the solutionwas Example II added to 500 ml. water; the product, 2-trichloromethyl-(a) A solution of 33.6 g. (0.4 mol) iminobutyronitrile 4133pammo-642411] endlno)ethy1)'s'triazine 74- in 350 ml. dioxane was addedat room temperature to a 76 Slowly crystaulzed solution of 36.8 g. (0.2mol) of cyanuric chloride in 200 PREFERRED EMBODIMENTS ml. of dioxane.The temperature increased to 45-50 C. whereby thellIllIlOdlflCfllZOIlltI'lle salt precipitated. The l'IllX- 10 While thes-triazines of Formula I how some dep -e5 lure Was filtered and the pipitate washed with hexane. sant eilects in mammals, there aredifferences both quan- Aftel' Concentrating the diOXaIlehhXahe filtrate,Of titative and qualitative exhibited by individual members "(l Slrifllille, of the class. Especially preferred depressants because ofcrystallized their activity as analgesics, muscle relaxants, anticonvul-To a SOhItiOh 0f gof the Product sants, and/ or tranquilizers are thes-triazine of Formula I of II(a) in 200 ml. dioxane was slowly added asolution h i Y i NHR Where R i lk l f 1 4 carbon of 9.0 g. (0.2 mol) ofethylamine in 100 ml. dioxane The atoms, r f bl ethyl or b 1 d Z iprecipitate was filtered and washed with water and after drying, yielded3-(4-chloro 6 ethylamino-s-triazin-Z- CH3 ylimino)butyronitrile, M.P.16772 C.

The compound 3-(6-tert-butylamino 4 chloro-s-tri- C(OH3)ZOH orTN=CTCHZCN azin-Z-ylimino)-butyronitrile, M.P. 115-25 C. was similarlyprepared using tert-butylamine. Preferred s-triazines within thissubclass are:

Example HI Z-trichloromethyl-4-ethylamino-6(l-hydroxy-l-methyl- To asolution of 43.3 g. (0.1 mol) of 2,4,6-tris-triethyl)-s-triazinechlorornethyl-s-triazine in 400 ml. methanol was added3-(4-chloro-6-ethylamino-s-triazin-Z-ylimino) butyroni- 25.5 g. (0 .3mol) of piperidine. After warming, a solution trile of 1 g. of sodium in20 ml. methanol was added and the3-(6-tert-butylamino-4-chloro-s-triazin-2-ylimino) bumixture wasrefluxed for 4 hours. After cooling the prodtyronitrile uct 2trichloromethyl 4-piperidino-fi-methoxy-s-triazine, M.P. 118120 C.,precipitated out. The following examples are presented to illustratecertain pharmacological responses induced by triazine com- Example IVpositions of the invention. These examples should in no (a) 10 g. (0.11mol) of 3-methoxypropylamine was way be regarded as limiting the scopeof the invention. added to a solution of 43.5 g. (0.1 mol) of2,4,6-tris- The results of the various pharmacological responsestrichloromethyl-s-triazine. After a short time, 2,6-bis-tritested areshown in Table I.

TABLE I Antieonvulsant Muscle relaxant, response(e) tranquilizationresponse(d) Maximal electro- Anti- Analgesic Pernicious shock strychnineresponse preenlng SGIZUI'G I'GSIJODSG Approximate intra- Muscleantagonism antagonism ratio based Approximate muscle perit0neal(c)relaxant based on based on on EDso analgesic relaxant analgesic ratingEDm i.p. ED i.p. i.p. or 180 dose, oral(a), dose, oral(b), rating at atIOOmgJ or32mg./ or 1001T 1g./ mg./ kg. mg./kg. mgJkg. 100 mgJkg. kg.i.p. kg. Lp. kg. i.p. 1.1)

Test compound +QQO+ 1 Numbers correspond to numbered triazines in 0015.2 and 3.

chloromethyl-4- 3 -methoxypropylamino -s-triazine, M.P. 112-115 C.,crystallized out.

(b) 40.3 g. (0.1 mol) of the IV(a) product in 250 ml. methanol wasrefluxed for 12 hours with 18.3 g. (0.3 mol) ethanolamine and thenconcentrated. After the residue was triturated with a acetone-watersolution (1:1), the product 2 trichloromethyl-4-(3-methoxypropylamino)-6- (Z-hydroxyethylamine)-s-triazine, M.P. 94-960, crystallized out.

(a) Analgesic response-The process of an analgesic eiTect was identifiedas an absence of a struggling or phonating response to a manual pinch ofthe tail of treated mice. The laboratory white mice for each treatmentwere placed in individual compartments. The mice were orally intubatedwith the test compound at the dosage of 500 milligrams per kilogram, and15 minutes, 1 hour, 2 hours, 4 hours and 24 hours after treatment apinch of the tail was applied to each mouse. Any compound inducing ananalgesic response in 50 percent of the mice at any of these testintervals was considered active in this test. Some of the compounds weretested at lower dosages.

While the exact safety factor has not been evaluated for all compoundsof the invention, it has been found that the elfective analgesic dose ofthe triazines of the invention is considerably lower than the toxic dose(LD (b) Muscle relaxant response.-As in (a) above, mice were orallyintubated with the test compound and the muscle relaxant effects of thecompounds were evaluated. The procedure for assessing skeletal musclerelaxant activity involves an evaluation of passivity, fiaccidity andpinnal reflex blockage. Passivity is defined as an absence of thestruggle behavior of the animal when manipulated manually and mayindicate skeletal muscle relaxation, central depression,tranquilization, paralysis, or anesthesia. Flaccidity is measured by thedecreased tonus of skeletal musculature and may indicate myorelaxantactivity, central depression, or paralysis. The pinnal reflex is testedby touching the inner aspects of the ear with a fine wire to elicit acharacteristic ear twitch. An impairment of this reflex suggests aninhibition of polysynaptic reflexes.

(c) Analgesic responceintraperitoneal.The analgesic response wasdetermined in laboratory white mice by injection of the triazines undertest at an intraperitoneal dosage of 100 mg. per kg. The results wereobtained by evaluation similar to that described for the ApproximateAnalgesic DoseOral. The compounds were rated on a one plus to four plus(+++f+) scale. When 1-2 mice out of ten showed an analgesic response, arating was assigned; indicated that 3-6 out of ten mice responded;indicated that 7-9 out of ten responded; while a rating meant that allten mice gave an analgesic response at the dosage tested.

(d) Muscle relaxanttranquilization response.The muscle relaxant effects,as expressed by passivity, flaccidity and pinnal reflex blockage, wereassessed in laboratory mice injected intraperitoneally with 100 mg./kg.of the test compound as in (b). In addition the tranquilizing eifects ofthe compounds under test were evaluated by the pernicious preening test(Wilton, I. G. et a1. Fed. Proc. 19:20, 1960). The pernicious preeningbehavior was elicited by painting the rear of the mice with apilocohesive dye. A violent unremitting tearing of the stiff, coheringstrands of hair constitutes the pernicious preening behavior. Thirtyminutes after injection, the pilocohesive dye was applied and thepresence or absence of the compulsive behavior was noted for a minuteinterval. The ratings for the muscle relaxant response are based uponthe scale given in (0). Effective antagonism of pernicious preening isshown with the same scale as in (c). That is, l-2 mice out of ten, ++=36mice out of ten, +++=79 mice out of ten and ++++=10 mice out of tenresponded. Some of these values for the individual triazines weredetermined at a dosage of 32 mg./kg. while the others were determined onthe basis of ED values, the dose at which 50 percent of the treatedanimals exhibit an effective response. These ED values were thentranslated into the +1 to +4 scale by the following criteria: ED valuesof 30-100 mg./kg.:+, 10-30 mg./kg.=++, 3-10 mg./kg.=+++ and 3mg./kg.:++++.

(e) Anticonvulsant response.The test procedures used were maximalelectroshock and antistrychnine assay methods. The test compound wasintraperitoneally injected into laboratory mice and after 30 minutes theanticonvulsant activity was measured. The technique employed in themaximal electroshock method was essentially that of Swinyard, E. A., J.Amer. Pharm. Assoc. 381201 (1949). The mice were subjected to analternating current stimulus, about equal to three times the currentnecessary to produce maximal seizures, and prevention of hindlimb tonicextensor phase was considered to be an effective anticonvulsant action.In the antistrychnine assay, the mice were intraperitoneally injectedwith the test compound and then were challenged with a lethalintraperitoneal dose of strychnine sulfate. Increase in survival timeagainst the lethal action of strychnine of greater than three standarddeviations of the control mean was considered an effective atcion.Anticonvulsant activity in these tests suggests skeletal musclerelaxation or efficacy against epileptic seizures. Effective antagonismof maximal electroshock seizure and antistrychnine activity are given onthe same +1 to +4 scale as in (c). Some of these values for theindividual triazines in the maximal electroshock seizure test weredetermined at a dosage of 100 mg./kg. while the others were determinedon the basis of ED values, the dose at which 50 percent of the treatedanimals exhibited an effective response. These ED values were thentranslated into the +1 to +4 scale by the following criteria: ED valuesof -300 mg./kg.=+, 30-100 mg./ kg.=+-|-, 10-30 mg./kg.=+++ and Theantistrychnine activities for the individual triazines were alsodetermined in either of two ways. Some are based on the response ratioat mg./kg. while the others on the ED values. The criteria fortranslating the ED values to the +1 to +4 scale is the same as for themaximal electroshock seizure test.

We claim as our invention:

1. A depressant veterinary and pharmaceutical composition comprising a(a) compound of the formula wherein X is C1 or --CCl Y is -NRR in whichR is hydrogen, alkyl of l-3 carbon atoms or hydroxyalkyl of l-4 carbonatoms,

R is alkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms,chloroalkyl of l-3 carbon atoms or methoxyalkyl of 2-5 carbon atoms andR and R together with the nitrogen may represent piperidino; and

Z is

in which R is alkyl of l-3 carbon atoms and R is hydrogen oralkoxycarbonyl of up to 4 carbon atoms;

t N(alkylenc)R4 in which R; is dialkylaminocarbonyl of up to 7 carbonatoms or alkylsulfinyl of 1-3 carbon atoms and alkylene is of 1-3 carbonatoms;

IiI N-R5-0H in which R is alkylene of l-4 carbon atoms;

in which m is 2-4;

O-alkyl in which alkyl is of l-3 carbon atoms;

H 1 TalkyleneOl in which alkylene is of 1-3 carbon atoms;

l a N=CCH2-CN in which R is alkyl of 1-3 carbon atoms and (b) aphysiologically acceptable carrier, the percent by Weight of (a) in thetotal formulation being from about one to about 95. 2. The veterinaryand pharmaceutical composition of claim 1 wherein R is hydrogen and R isalkyl of 1-4 carbon atoms and Z is wherein X is C1 or CCl Y is NRR inwhich R is hydrogen, alkyl of 1-3 carbon atoms or hydroxyalkyl of 1-4carbon atoms, R is alkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbonatoms, chloroalkyl of 1-3 carbon atoms or methoxyalkyl of 2-5 carbonatoms and R and R together with the nitrogen may represent piperidino;and Z is R2 --ORa in which R is alkyl of 1-3 carbon atoms and R ishydrogen or alkoxycarbonyl of up to 4 carbon atoms;

10 F -N(alkylene)-R in which R; is dialkylaminocarbonyl of up to 7carbon atoms or alkylsulfinyl of l-3 carbon atoms and alkylene is of 1-3carbon atoms;

N-Ra0]1 in which R is alkylene of 1-4 carbon atoms;

in which m is 2-4; CCl O is allyl in which alkyl is of 1-3 carbon atoms;

N-alky1ene- C1 in which alkylene is of 1-3 carbon atoms;

i N=CCH2CN in which R is alkyl of 1-3 carbon atoms. 7. The method ofclaim 6 wherein said compound is administered orally to said mammal.

8. The method of claim 6 wherein said compound is administeredparenterally to said mammal.

9. The method of claim 6 wherein R is hydrogen and R is alkyl of 1-4carbon atoms and Z is r C(CH3)2OH or N= CCI-lzCN 10. The method of claim9 wherein X is trichloromethyl, R is ethyl and Z is -C(CH OH.

11. The method of claim 9 wherein X is chlorine, R is ethyl and Z is 12.The method of claim 9 wherein X is chlorine, R is tert-butyl and Z is3113 N=O-CH2CN References Cited UNITED STATES PATENTS 2,867,621 1/ 1959Grundmann 260-249.5 2,909,420 10/1959 Gysin et a1. 260249.5 3,086,8554/1963 Knusli et a1. 260249.9

FOREIGN PATENTS 222,552 7/1959 Australia 260249.8 631,493 11/1961 Canada260-2499 1,329,306 4/1963 France 260249.5

ALBERT T. MEYERS, Primary Examiner DAREN M. STEPHENS, Assistant Examiner

